Multiple organ failure (MOF) is the leading cause of death in injured patients admitted to the ICU. Although its precise genesis in unknown, ongoing work in our laboratory and others demonstrates that end-organ injury in MOF is due to an unbridled systemic inflammation response (SIRS). Our most recent work suggests that biologically active lipids and cytokins present in banked blood components exacerbate postinjury SIRS by priming circulating neutrophils and tissue endothelium. This concept is supported by a published analysis of our trauma patient database which shows that blood transfusion in an independent risk factor for MOF. The current clinical use of lipid-free, cytokine-free blood substitute (Polyheme) is a phase II/III trial provides us with the unique opportunity to study how avoiding the use of banked red blood cells (pRBCs) during resuscitation of the injured patient might attenuate postinjury hyperinflammation. Preliminary data on the functional response of isolated neutrophils from these patients is encouraging. We are requesting the expert technical assistance of the CRC core laboratory in the analysis of circulating cytokines, cytokine receptors and markers of endothelial injury/activation in critically ill patients given Polyheme or pRBCs.